Automated method and apparatus for preparing bioprocess solutions

ABSTRACT

An automated apparatus for preparing a liquid bioprocess solution includes at least one mixing chamber having a lower port and an upper port for fluid to enter the at least one mixing chamber, an array of tubing for fluid flow within the system, a plurality of valves provided within the tubing, and a mixing controller configured to cause the automated apparatus to perform a series of sequential mixing steps causing the preparation of the liquid bioprocess solution from a dry ingredient. The series of sequential mixing steps include opening a first valve associated with the lower port to provide fluid to the at least one mixing chamber through the lower port, and after a predetermined amount of elapsed time, closing the first valve and opening a second valve associated with the upper port to provide fluid to the at least one mixing chamber through the upper port.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.16/017,014, filed Jun. 25, 2018, which claims priority to U.S.Provisional Patent Application Ser. No. 62/527,878, filed Jun. 30, 2017,which applications are each incorporated herein by reference in itsentirety.

BACKGROUND

Embodiments of the present technology generally relate to an automatedmethod and apparatus for mixing at least one material with at least onefluid. More particularly, embodiments of the present technology relateto an automated method and apparatus specifically adapted forreconstituting dry ingredients in predetermined unit volume amounts intobioprocess solutions.

A bioprocess is a process that uses living cells or their components toobtain desired products. Bioprocesses often require the use of varioussolutions. For example, the initial steps in a bioprocess may involvecell culturing, and cell culturing often requires the use of cellculture media to successfully cultivate new cells. Later steps in abioprocess may then require the use of various buffer solutions as partof a product purification process.

Bioprocess solutions are often hydrated from dry ingredients immediatelybefore use either in large stainless steel tanks or in single-use mixingdevices. The typical process is time consuming, expensive and adds nodirect value to the desired product.

While the basic cell culture methods have not changed appreciably overthe years, the volumes of cell cultures continue to increasedramatically, thereby changing the requirements for media preparation.Not only are more research laboratories, pharmaceutical, andbiotechnology companies employing cell culture methods, but they areoften doing so on a very large scale. A biotechnology company mayconsume many thousands of liters of liquid media a day and employ largenumbers of manufacturing technicians and scientists to produceantibodies, growth factors, or recombinant proteins from cell culturefor commercial use. The present invention provides an automated systemand method for employing an in-line mixing device to prepare bioprocesssolutions that can help reduce the required time, labor, risk of errorand risk of contamination in these processes while also improvingreliability and consistency.

SUMMARY OF THE INVENTION

Generally, embodiments described herein relate to automated methods andapparatuses for preparing dry ingredients into liquid solutions (e.g.,preparing powdered bioprocess media into liquid bioprocess media). Asdiscussed further below, dry ingredients tend to require less storagespace than reconstituted, liquid solutions, have longer shelf lives, beless expensive, and require less shipping and handling time thanprepackaged liquid solutions. Thus, when liquid solutions are needed, itis advantageous to utilize automated methods and apparatuses designed tomake the preparation of liquid solutions from dry ingredients simple,straightforward, and repeatable, rather than purchase prepackaged liquidsolutions. Accordingly, the technology according to some embodimentsrelates to an automated method to be used with a mixing apparatus formixing dry ingredients (e.g., a powdered media) into a fluid, such ascell culture media or buffers. More particularly, some embodiments ofthe present technology relate to an automated method to be used with amixing apparatus where both the automated method and the mixingapparatus are adapted for reconstituting dry ingredients into liquids inpredetermined unit volume amounts.

A variety of dry ingredients may be reconstituted into liquid solutionsusing the present technology. For example, as used herein, dryingredients may refer to powdered cell culture media, dry powder media,dry buffer powder, granulated media, dry salts, dry chemicals, drycomponents, dry materials, and unhydrated ingredients.

Some embodiments described herein are based, at least in part, upon somedeficiencies and/or inconveniences with existing reconstitutiontechnologies, as recognized by the inventors of the instant technology,or based upon the recognition of potential improvements by theinventors. For example, prepackaged liquid cell culture media can besterile and aliquoted into convenient sizes and may come ready to use.However, prepackaged liquid cell culture media are typicallylight-sensitive and have a prescribed shelf-life. Therefore, prepackagedliquid cell culture media must be ordered on a regular basis. They alsoshould be stored under refrigeration and, in their prepackaged form,require significant manpower time to un-package and transport. Further,shipping costs of prepackaged liquid cell culture media are becomingincreasingly more expensive.

By contrast, powdered cell culture media are provided in bulk or inpremeasured packages. They tend to have a longer shelf life, be lessexpensive, and require less storage space and shipping and handling timethan when in liquid form. However, powdered cell culture media must bereconstituted into liquid cell culture media by aliquoting anddissolving the powdered media under sterile conditions. The increasedhandling and preparation time for powdered cell culture media,especially for large volume media preparation, often makes prepackagedliquid cell culture media the preferred choice despite the increasedcost.

Furthermore, reconstitution of dry ingredients into a liquid bioprocesssolution generally is a several step process. As an example, to prepareliquid cell culture media from a solid powder, a known amount of powderintended for a specific volume of media is measured out and added to avolume of distilled water that is typically less than the final desiredvolume. The powder and water are stirred until the solid is completelydissolved. A specific quantity of sodium bicarbonate is added anddissolved. The pH may thereafter be adjusted using an acid or base, andadditional water is added to increase the media to its final volume. Theentire mixture is then passed through a sterilizing filter. The mediamay thereafter be collected in a single large sterile vessel orproportioned into several smaller sterile vessels.

There may be further difficulties in reconstituting solutions based oncharacteristics of the dry ingredients being reconstituted. For example,powdered tissue culture media have very fine particle sizes and arehygroscopic. When mixed with water, they have the tendency to “ball” or“clump.” Thus, when reconstituting in water or another aqueous liquid,sufficient agitation is required to break up any clumps that may formupon initial contact with water. For smaller batch sizes, sterilemagnetic stir bars can be added to the mixing container, and thecontainer is then placed on a magnetic stir plate. Additionalmanipulations usually are required to add stir bars to the mixingcontainers. In a typical laboratory setting, however, magnetic stirplates are not a practical solution for large volume media preparation.

In addition, due to their hygroscopic nature, powdered cell culturemedia absorb water when stored, especially in humid environments. Wetpowdered media have shortened shelf lives, become lumpy, and requireaggressive agitation to reconstitute. Thus, powdered cell culture mediashelf life could be improved if they were provided in premeasured,sealed, and desiccated aliquots.

Further, the reconstitution process requires several steps and severalseparate pieces of equipment. It generally requires at least one vessel,large enough to contain the entire final volume of reconstituted media,plus one or more vessels to receive the sterile media after filtration.The sterilized media are usually delivered into open top containers.Thus, most media preparation is done in a laminar flow hood. Processinglarge volumes of media in a hood is difficult, however, because there isoften not enough space to accommodate the containers and sterile media.Accordingly, a method and a device permitting the preparation of largevolumes of solutions (e.g., cell culture media) with minimal physicalcontact and in a reliable and repeatable way are described herein.

One embodiment of the technology relates to an automated method. Theautomated method includes providing a dry ingredient to be reconstitutedinto a liquid bioprocess solution and controlling, by a processingcircuit, an automated system including at least one mixing chamber, anarray of tubing for fluid flow within the system, and a plurality ofvalves provided within the tubing, to automatically prepare the liquidbioprocess solution from the dry ingredient. Controlling the automatedsystem may include performing a series of sequential mixing steps, theseries of sequential mixing steps causing the preparation of the liquidbioprocess solution. The method may further include taking one or moremeasurements during the preparation of the liquid bioprocess solution,wherein each step is triggered by at least one of a measurementdecreasing below, equaling, or exceeding a measurement threshold. Eachstep may also include opening or closing, by the processing circuit, atleast one of the plurality of valves to control fluid flow within theautomated system. The bioprocess solution may be cell culture media or abuffer solution.

A second embodiment of the technology relates to an automated method.The automated method includes providing a dry ingredient to bereconstituted into a liquid bioprocess solution and providing anautomated system including at least one mixing chamber, an array oftubing for fluid flow within the system, a plurality of valves providedwithin the tubing, and one or more inlets to the tubing. The automatedmethod also includes coupling a purified water sources to one of the oneor more inlets. The automated method further includes controlling, by aprocessing circuit, the automated system to prepare a liquid bioprocesssolution from the dry ingredient by performing a series of sequentialmixing steps, each step comprising opening or closing at least one ofthe plurality of valves to control fluid flow within the automatedsystem, and taking one or more measurements during the preparation ofthe liquid bioprocess solution, wherein each step is triggered by atleast one of a measurement decreasing below, equaling, or exceeding ameasurement threshold. The bioprocess solution may be cell culture mediaor a buffer solution.

A third embodiment of the technology relates to an automated apparatusfor preparing a liquid bioprocess solution from a dry ingredient. Theautomated apparatus includes at least one mixing chamber, an array oftubing, a plurality of valves provided within the tubing, and a mixingcontroller. The mixing controller includes at least a processor and amemory with instructions stored thereon, the mixing controllerconfigured to control the plurality of valves to prepare a liquidbioprocess solution from a dry ingredient. The automated apparatus mayalso include one or more sensors configured to take one or moremeasurements during preparation of the liquid bioprocess solution,wherein the mixing controller is configured to control the plurality ofvalves in response to at least one of a measurement decreasing below,equaling, or exceeding a measurement threshold. The bioprocess solutionmay be cell culture media or a buffer solution.

A fourth embodiment of the technology relates to an automated method.The automated method includes providing a bioprocessing buffer in a dryformat and controlling, by a processing circuit, an automated systemcomprising at least one mixing chamber, an array of tubing for fluidflow within the system, and a plurality of valves provided within thetubing, to automatically prepare a liquid bioprocessing buffer from thebioprocessing buffer in the dry format. Controlling the automated systemmay include performing, by the processing circuit, a series ofsequential mixing steps, the series of sequential mixing steps causingthe preparation of the liquid bioprocessing buffer. The method mayfurther include taking one or more measurements during the preparationof the liquid bioprocessing buffer, wherein each step is triggered by atleast one of a measurement decreasing below, equaling, or exceeding ameasurement threshold. Each step may also include opening or closing, bythe processing circuit, at least one of the plurality of valves tocontrol fluid flow within the automated system.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned features, as well as other features, aspects, andadvantages, of the present technology will now be described inconnection with various embodiments of the invention, in reference tothe accompanying drawings. The illustrated embodiments, however, aremerely examples and are not intended to limit the invention.

FIGS. 1A and 1B are schematic representations of a mixing apparatus tobe used with an automated reconstitution method for a bioprocesssolution.

FIG. 2 is a schematic diagram of a mixing controller to be used with themixing apparatus of FIGS. 1A and 1B.

FIG. 3 is a flow diagram illustrating an automated method forreconstituting powdered cell media.

FIGS. 4A-4G are schematic representations of the mixing apparatus ofFIGS. 1A and 1B depicting steps of the automated method of FIG. 3.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part of the present disclosure. Inthe drawings, similar symbols typically identify similar components,unless context dictates otherwise. The illustrative embodimentsdescribed in the detailed description, drawings, and claims are notmeant to be limiting. The detailed description is intended as adescription of exemplary embodiments and is not intended to representthe only embodiments that may be practiced. The term “exemplary,” asused herein, means “serving as an example, instance, or illustration”and should not necessarily be construed as preferred or advantageousover other embodiments. Other embodiments may be utilized, and otherchanges may be made, without departing from the spirit or scope of thesubject matter presented herein. It will be readily understood that theaspects of the present disclosure, as generally described herein andillustrated in the Figures, can be arranged, substituted, combined, anddesigned in a wide variety of different configurations, all of which areexplicitly contemplated and form part of this disclosure.

Embodiments described herein generally relate to devices/apparatuses,systems, and methods for the preparation of solutions from dryingredients, for example, media for cell culture from dry powdered cellculture media or buffer solutions from dry buffer powder. One or more ofthe provided embodiments may overcome one or more of the drawbacks,limitations, or deficiencies that exist in the art with respect toreconstituting solutions, particularly with respect to reconstitutingcell culture media in a dry format, including dry powder media. Forexample, in some embodiments described herein, an automated method andapparatus may permit mixing of dry ingredients into a liquid bioprocesssolution such that the mixing process is easy to use, can be used toreconstitute relatively large quantities of solution, and results in asolution that is thoroughly mixed and not clumped.

The present disclosure makes reference to the systems and methodsdescribed herein in the context of preparing liquid cell culture mediafrom powdered cell culture media. However, it should be understood thatthe systems and methods described herein can be adapted to preparingother types of solutions. For example, the systems and methods describedherein may be used to prepare buffers for chromatography and downstreamprocessing of biopharmaceutical bulk drug substances. As anotherexample, the systems and methods described herein may be used to preparevarious “bioprocess solutions,” or solutions that are used in processesof using living cells or their components to obtain desired products.Moreover, it is contemplated that the systems and methods describedherein may be adapted for a number of broader commercial or industrialapplications. As an example, many liquid pharmaceuticals are prepared inthe hospital pharmacy with some frequency and quantity. Salinesolutions, alimentary preparations, imaging reagents, dyes,sterilization solutions, and anesthetics are reconstituted as liquids.Additional alternative applications include, but are not limited to,preparation of pesticides, fertilizers, and any of a variety ofbeverages commonly prepared from powder (e.g., milk, iced tea, etc.),all of which could be reconstituted using embodiments of the systems andmethods described herein. In this regard, dry ingredients that may bereconstituted using the present systems and methods are not limited topowdered cell culture media and may include dry powder media, dry bufferpowder, granulated media, dry salts, dry chemicals, dry components, drymaterials, and unhydrated ingredients.

FIG. 1A is an overall system view of one embodiment of a mixingapparatus 10. Preferably, the mixing apparatus 10 is made of materialsthat are appropriate for the cell culture environment, such asnon-toxic, medical grade plastics or other non-toxic materials that willnot contaminate the media. The mixing apparatus 10 includes a firstmixing chamber 12, a second mixing chamber 14, and a filter unit 16connected together with various lengths of tubing (e.g., flexiblehoses). As discussed in further detail below, the tubing furtherincludes various valves provided therein for selectively allowing (e.g.,when the valve is in an open position) and stopping (e.g., when thevalve is in a closed position) the flow of fluids through the valves. Inan exemplary embodiment, the valves are pinch valves, though in otherembodiments, the valves may be or include other types of valves, such asball valves. In various embodiments, the mixing apparatus 10 is designedfor reconstitution of powdered cell culture media into liquid media. Forexample, the mixing apparatus 10 may be a single use apparatus withnecessary media components (e.g., powdered cell culture media, sodiumbicarbonate, etc.) prepackaged therein. However, those of skill in theart will appreciate that the mixing apparatus 10 may also be used toreconstitute other forms of undissolved cell culture media (e.g.,granulated cell culture media), prepare bioprocessing buffers from a dryformat, or more generally reconstitute liquids from powders.

To begin with, in various embodiments, the first mixing chamber 12contains dry powder media to be reconstituted into liquid media. It iscontemplated that the first mixing chamber 12 will be provided with apremeasured amount of dry powder media. In some embodiments, the firstmixing chamber 12 may be prepackaged with the premeasured amount of drypowder media already therein. Additionally, in various embodiments, thefirst mixing chamber 12 is designed to facilitate mixing of the mediawith purified water and/or with other powders or liquids, such asdissolved sodium bicarbonate or a supplement. For example, the firstmixing chamber 12 may include a top and/or bottom cone coupled to thetop and/or bottom end, respectively, of the first mixing chamber 12 tofacilitate the creation of a swirling vortex motion as fluid enters thefirst mixing chamber 12. The swirling vortex motion helps facilitate themixing of the dry powder media, the purified water, dissolved sodiumbicarbonate, a supplement, etc. Various configurations and embodimentsof the first mixing chamber 12 are described in U.S. application Ser.No. 15/087,826 titled “Media Mixing Chamber,” filed on Mar. 31, 2016,and hereby incorporated herein in its entirety.

The first mixing chamber 12 includes three ports whereby fluids may flowinto and out of the first mixing chamber 12: a top port 20, an upperport 22, and a lower port 24. In exemplary embodiments, the ports 22 and24 are positioned on the first mixing chamber 12 such that fluids enterthe first mixing chamber 12 through the ports 22 and 24 at substantiallya tangential angle to an inner wall of the first mixing chamber 12,which may further facilitate the mixing of various media components inthe first mixing chamber 12.

A top inlet/outlet tube 30 is coupled to the first mixing chamber 12 atthe top port 20. As shown in FIG. 1A, the top inlet/outlet tube 30connects the first mixing chamber 12 to a common inlet tube 32 and anupper filter inlet tube 34. In turn, the common inlet tube 32 connectsto a supplement inlet tube 36 and a compressed air inlet tube 38. Thesupplement inlet tube 36 is configured to couple to a supplement source(not shown) at a supplement entry 40. The supplement source may containany type of supplement used in cell culture media, such as an amino acidsupplement, a cholesterol supplement, a lipid supplement, etc. Thecompressed air inlet tube 38 is configured to couple to a compressed airsource (not shown) at a compressed air entry 42. Accordingly, whenfluids (e.g., media supplements, compressed air) are introduced to theapparatus 10 by the supplement inlet tube 36 and by the compressed airinlet tube 38, the fluids flow to the common inlet tube 32. The fluidsthen flow to the top inlet/outlet tube 30 and into the first mixingchamber 12 by the top port 20.

As shown in FIG. 1A, the compressed air inlet tube 38 also includes acompressed air valve 44. When in an open position, the compressed airvalve 44 allows compressed air to flow from the compressed air sourcethrough the compressed air valve 44 to the first mixing chamber 12, asdescribed. Conversely, when the compressed air valve 44 is in a closedposition, the compressed air valve 44 prevents compressed air fromflowing through the valve 44. However, as further shown in FIG. 1A, thesupplement inlet tube 36 does not include a valve. Thus, unlikecompressed air, supplement is able to flow to the first mixing chamber12 whenever supplement is introduced to the apparatus 10 by thesupplement inlet tube 36.

An upper inlet tube 46 is coupled to the first mixing chamber 12 at theupper port 22. The upper inlet tube 46 connects to a fluid inlet tube48. The water inlet tube 48 is configured to couple to a fluid source(not shown) by a fluid entry 50. In an exemplary embodiment, the fluidsource contains and provides purified water (e.g., distilled deionizedwater (ddH₂O)). In an exemplary embodiment, the water source contains atleast 1,000 L of purified water. Additionally, the upper inlet tube 46includes an upper inlet valve 52. As such, when the upper inlet valve 52is in an open position and water is introduced to the apparatus 10 bythe water inlet tube 48, the water flows from the water inlet tube 48,through the open upper inlet valve 52, and into the upper inlet tube 46.From the upper inlet tube 46, the water flows into the first mixingchamber 12 by the upper port 22. When the upper inlet valve 52 is in aclosed position, water cannot flow to the first mixing chamber 12 by theupper port 22.

As shown in FIG. 1A, the water inlet tube 48 further connects to a lowerflow tube 54, a second chamber tube 56, and a lower filter tube 58. Thelower flow tube 54 is coupled to the first mixing chamber 12 by thelower port 24, and a second chamber outlet tube 60 branches from thelower flow tube 54 partway down the length of the lower flow tube 54.The lower flow tube 54 further includes a lower port valve 62 proximateto the tubing section where the water inlet tube 48, the lower flow tube54, the second chamber tube 56, and the lower filter tube 58 connect.Thus, when the lower port valve 62 is in an open position, fluids canflow into and out of the first mixing chamber 12 through the lower flowtube 54 and the lower port 24, but when the lower port valve 62 is in aclosed position, fluids cannot flow past the valve 62.

The second mixing chamber 14 contains an additive to the cell culturemedia. In an exemplary embodiment, the second mixing chamber 14 containssodium bicarbonate powder, and the second mixing chamber 14 is designedto facilitate mixing of the sodium bicarbonate with purified water.Additionally, the second mixing chamber 14 may be prepackaged with apremeasured amount of sodium bicarbonate therein. In some embodiments,the second mixing chamber 14 is configured similarly to the first mixingchamber 12 (e.g., including a top and/or bottom cone coupled to the topand/or bottom end, respectively, of the second mixing chamber 14 tofacilitate the creation of a swirling vortex motion as fluid enters thesecond mixing chamber 14). In other embodiments, the second mixingchamber 14 is configured differently from the first mixing chamber 12.Various configurations and embodiments of the second mixing chamber 14are described in U.S. application Ser. No. 15/087,826 titled “MediaMixing Chamber,” filed on Mar. 31, 2016, which as noted above isincorporated herein in its entirety.

The second mixing chamber 14 includes two ports whereby fluids may flowinto and out of the second mixing chamber 14: a second chamber top port64 and a second chamber lower port 66. In exemplary embodiments, theport 66 is positioned such that fluids enter the second mixing chamber14 by the port 66 at substantially a tangential angle to an inner wallof the second mixing chamber 14, which may further facilitate the mixingof the sodium bicarbonate and the purified water in the second mixingchamber 14.

As shown in FIG. 1A, the second chamber outlet tube 60 is coupled to thesecond mixing chamber 14 at the second chamber top port 64. The secondchamber outlet tube 60 also includes a second chamber outlet valve 68proximate to where the second chamber outlet tube 60 branches from thelower flow tube 54. Additionally, as shown in FIG. 1A, the secondchamber tube 56 is coupled to the second mixing chamber 14 at the secondchamber lower port 66. The second chamber inlet tube 56 further includesa second chamber inlet valve 70 proximate to the tubing section wherethe water inlet tube 48, the lower flow tube 54, the second chamber tube56, and the lower filter tube 58 connect. Accordingly, fluids (e.g.,purified water from the water source) can only flow into and out of thesecond mixing chamber 14 when the second chamber inlet valve 70 and thesecond chamber outlet valve 68 are in open positions. When the secondchamber inlet valve 70 and the second chamber outlet valve 68 are inclosed positions, fluids cannot flow into or out of the second mixingchamber 14.

The lower filter tube 58 connects the tubing section where the waterinlet tube 48, the lower flow tube 54, the second chamber tube 56, andthe lower filter tube 58 meet to the upper filter inlet tube 34, atwhich point the lower filter tube 58 and the upper filter inlet tube 34merge. The merged lower filter tube 58 and upper filter inlet tube 34then connect to the filter unit 16. As shown in FIG. 1A, the filter unit16 includes a filtration tubing section 72 whereby the filter unit 16couples to the merged lower filter tube 58 and upper filter inlet tube34. The filtration tubing section 72 is also coupled to an outlet 74,which ends in an apparatus exit 76. The apparatus exit 76 is configuredto couple to a collection vessel that collects the media solution mixedand outputted by the apparatus 10. In various embodiments, thecollection vessel may be made of glass, plastic, or metal and may bepre-formed or flexible.

The filter 16 is configured to filter solution flowing into the filterby the filtration tubing section 72. For example, the filter 16 mayremove undissolved powdered media from the solution by a membrane in thefilter 16. The filter 16 may be further configured to sterilize thesolution flowing into the filter before the solution flows out of theapparatus by the outlet 74. Additionally, because air will not passthrough the membrane of the filter 16 once the filter 16 is wet, thefilter 16 may further include a top segment with a hydrophobic vent thatallows air to escape the filter 16. This vent prevents air from becomingtrapped in the filter 16, hindering the filtration process.

Filters of the type contemplated by this technology can be purchasedfrom a number of suppliers. For example, the filter 16 may comprisenylon or cellulose acetate. Additionally, for a media product, thefilter 16 will typically be a 0.2μ filter, though it is contemplatedthat other filter sizes could be chosen for certain functions. Forexample, the preparation of electrophoretic buffers requires clean, butnot necessarily sterile solutions, and a 0.45μ filter would be adequate.Similarly, the preparation of more viscous solutions may necessitate awider pore size. In short, the filter 16 can be of any desired size,volume, pore size, and so forth. Moreover, for other applications of thetechnology disclosed herein, no filtration apparatus may need to beadded. Liquid then passes directly to the collection vessel through theoutlet 74. Alternatively, in some embodiments, a hydrophobic vent filteris employed at some point before the filter 16 in order to allow the airthat is entrained in the dissolved medium to vent so that it does notfill the filter 16.

As shown in FIG. 1A, the lower filter tube 58 further includes a waterbypass valve 78 proximate to the tubing section where the water inlettube 48, the lower flow tube 54, the second chamber tube 56, and thelower filter tube 58 connect. As such, when the water bypass valve 78 isin an open position and the water source is open, fluid flows from thefluid source through the water inlet 48 and into the lower filter tube58. From the lower filter tube 58, the fluid flows into the filter 16 bythe filtration tubing section 72. In this way, fluid may bypass both thefirst mixing chamber 12 and the second mixing chamber 14 and flowdirectly to the filter 16 (e.g., to alleviate filter 16 backpressure).When the water bypass valve 78 is in a closed position, the water bypassvalve 78 prevents fluids (e.g., water from the water source, bicarbonatesolution mixed by the second mixing chamber 14) from bypassing the firstmixing chamber 12 and flowing directly to the filter 16.

As also shown in FIG. 1A, the upper filter inlet tube 34 additionallyincludes an upper filter inlet valve 80. Accordingly, when the upperfilter inlet valve 80 is in an open position, the upper filter inlettube 34 allows the flow of fluids through the upper filter inlet tube 34to the filter 16. More specifically, when the first mixing chamber 12fills with solution (e.g., a solution of purified water, powdered media,bicarbonate, and/or a supplement), the solution flows out of the firstmixing chamber 12 by the top port 20 and into the top inlet/outlet 30.The solution then flows into the upper filter inlet tube 34 and, whenthe upper filter inlet valve 80 is in the open position, flows into thefilter 16 by the filtration tubing section 72. On the other hand, whenthe upper filter inlet valve 80 is in a closed position, fluids cannotflow through the upper filter inlet tube 34 to the filter 16.

Additionally, in various embodiments, the mixing apparatus 10 mayinclude various sensors for taking measurements in the mixing apparatus10. These sensors may include, for example, pressure sensors (e.g., fordetecting water pressure within the apparatus 10), conductivity sensors(e.g., for detecting the conductivity, and thus the concentration, ofsolutions in the apparatus 10), volume sensors, such as a rotary flowmeter, (e.g., for detecting a volume and flow rate of fluid consumed inthe mixing process), pH sensors (e.g., for detecting the pH of solutionsin the apparatus 10), viscometers (e.g., for measuring the viscosity offluids in the apparatus 10), and so on. As shown in FIG. 1B, in anexemplary embodiment, the mixing apparatus 10 includes at least apressure sensor 90 located in the upper filter inlet tube 34, aconductivity sensor 92 located in the merged upper filter inlet tube 34and lower filter tube 58, and a volume sensor 94 located in the waterinlet tube 48. The pressure sensor 90 is configured to measure thepressure of the fluids flowing into the filter 16 (e.g., to ensure thatthe filter 16 backpressure does not become too high). The conductivitysensor 92 is configured to measure the conductivity of the solutionflowing into the filter 16, thereby indirectly measuring theconcentration of the solution flowing into the filter 16 and ultimatelyout of the apparatus 10. Finally, the volume sensor 94 is configured tomeasure the volume and flow rate of water consumed during the mixingprocess.

In various embodiments, as described in further detail below, thepowdered media are mixed into liquid media in the mixing apparatus 10through an automated method. Using the mixing apparatus 10 to prepareliquid media from dry powdered media through an automated method is animprovement over the current field, as it allows for easy and efficientliquid media preparation. Additionally, having programming logic (e.g.,implemented by a processing circuit executing instructions stored onnon-transitory machine readable media as part of a computing system)controlling the automated method makes the preparation of liquid mediafrom dry powdered media repeatable and consistent.

In an automated method, a computing system controls the opening andclosing of valves (e.g., valves 44, 52, 62, 68, 70, 78, and 80), as wellas sources of components used during the automated method (e.g., a watersource, a compressed air source, a supplement source), to control themixing of the powdered media into liquid media. The computing system mayopen and/or close valves and component sources in response to a varietyof triggers. For example, the computing system may receive measurementsfrom the mixing apparatus 10 relating to the mixing process (e.g., fromthe pressure sensor 90, the conductivity sensor 92, and the volumesensor 94). The computing system may then open and/or close valvesand/or component sources in response to receiving measurements ofcertain levels, below or above certain levels, within certain ranges,etc. As another example, the computing system may open and/or closevalves and/or component sources in response to certain amounts ofelapsed time.

Accordingly, FIG. 2 illustrates a computing system configured to controlthe mixing apparatus 10 according to an automated method, the computingsystem embodied as mixing controller 100. As shown in FIG. 2, the mixingcontroller 100 includes a communications interface 102 and a processingcircuit 104. The communications interface 102 is structured tofacilitate communications between the mixing controller 100 and externalsystems or devices. Thus, as shown in FIG. 2, the communicationsinterface 102 may receive data relating to the mixing process from agroup of sensors 150 included in the mixing apparatus 10, such aspressure data from the pressure sensor 90, conductivity data from theconductivity sensor 92, and volume/flow rate data from the volume sensor94. Additionally, the communications interface 102 may receive commandsfrom a user via a user device 170. For example, the communicationsinterface 102 may receive a command from the user via the user device170 to begin executing an automatic mixing method.

As further shown in FIG. 2, the communications interface 102 maytransmit commands to one or more of a group of valves 152, such asvalves 44, 52, 62, 68, 70, 78, and 80 discussed above. Similarly, thecommunications interface 102 may transmit instructions or commands to agroup of component sources 154, such as a water source 160 (e.g.,coupled to the water entry 50), a supplement source 162 (e.g., coupledto the supplement entry 40), and a compressed air source 164 (e.g.,coupled to the compressed air entry 42). For example, the communicationsinterface 102 may transmit instructions to open or close any valve inthe group of valves 152 or any component source in the group ofcomponent sources 154.

The communications interface 102 may include wired or wirelesscommunications interfaces (e.g., jacks, antennas, transmitters,receivers, transceivers, wire terminals, etc.) for conducting datacommunications with external systems or devices. In various embodiments,the communications may be direct (e.g., local wired or wirelesscommunications) or via a communications network (e.g., a WAN, theInternet, a cellular network, etc.). For example, the communicationsinterface 102 can include an Ethernet card and port for sending andreceiving data via an Ethernet-based communications link or network. Inanother example, the communications interface 102 can include a WiFitransceiver for communicating via a wireless communications network orcellular or mobile phone communications transceivers.

The processing circuit 104 includes a processor 106 and a memory 108.Processor 106 may be a general purpose or specific purpose processor, anapplication specific integrated circuit (ASIC), one or more fieldprogrammable gate arrays (FPGAs), a group of processing components, orother suitable processing components. Processor 106 is configured toexecute computer code or instructions stored in memory 108 or receivedfrom other computer readable media (e.g., CDROM, network storage, aremote server, etc.).

Memory 108 may include one or more devices (e.g., memory units, memorydevices, storage devices, etc.) for storing data and/or computer codefor completing and/or facilitating the various processes described inthe present disclosure. Memory 108 may include random access memory(RAM), read-only memory (ROM), hard drive storage, temporary storage,non-volatile memory, flash memory, optical memory, or any other suitablememory for storing software objects and/or computer instructions. Memory108 may include database components, object code components, scriptcomponents, or any other type of information structure for supportingthe various activities and information structures described in thepresent disclosure. Memory 108 may be communicably connected toprocessor 106 via the processing circuit 104 and may include computercode for executing (e.g., by processor 106) one or more processesdescribed herein. When processor 106 executes instructions stored inmemory 108 for completing the various activities described herein,processor 106 generally configures the mixing controller 100 (and moreparticularly processing circuit 104) to complete such activities.

The mixing controller 100 further includes a measurement controller 110and a method execution controller 112. As shown in FIG. 2, themeasurement controller 110 is configured to receive measurements fromthe group of sensors 150 via the communications interface 102.Additionally, in various embodiments, the measurement controller 110 isconfigured with an internal timer for keeping track of elapsed timeduring the execution of the automated method. The measurement controller110 provides one or more of the received measurements and/or the trackedelapsed time to the method execution controller 112 during the executionof the automated method. Additionally, the measurement controller 110may receive data from the method execution controller 112 during theexecution of the automated method that indicates the progress of theautomated method. For example, the measurement controller 110 mayreceive, from the method execution controller 112, an indication that agiven step of the automated method is currently being carried out.

The method execution controller 112 is configured to provide commands toone or more of the group of valves 152 and group of component sources154. In various embodiments, the method execution controller 112provides commands in response to (a) instructions from a user receivedvia the communications interface 102 and (b) data received from themeasurement controller 110. In one example, the method executioncontroller 112 may open and/or close certain valves of group 152 and/orcertain component sources of group 154 in response to a user instructionto begin executing the automated method. In a second example, the methodexecution controller 112 may open and/or close certain valves of group152 and/or certain component sources of group 154 in response to areceived measurement being at a certain level. In a third example, themethod execution controller 112 may open and/or close certain valves ofgroup 152 and/or certain component sources of group 154 in response to acertain amount of elapsed time. Additionally, the method executioncontroller 112 may be further configured to provide feedback data to themeasurement controller 110. For example, the method execution controller112 may provide a notification to the measurement controller 110indicating that a given step of the automated method has been executed.

FIG. 3 illustrates a flow diagram depicting an example of an automatedmethod 200 for using the mixing apparatus 10 to mix powdered media intoliquid media. FIGS. 4A-4G illustrate the flow of fluids through themixing apparatus 10 during the steps of the automated method 200. Asdescribed below, the sequence of steps illustrated in FIG. 3 and FIGS.4A-4E set forth a strict protocol for successful use of the mixingapparatus 10 to reconstitute powdered media into liquid media. Use ofthis strict protocol results in timing that is key to the success of theautomated method 200. For example, in an exemplary embodiment, themixing controller 100 uses the protocol of the automated method 200 tomix a powdered cell culture media volume less than 50% of the volume ofthe first mixing chamber 12.

However, those of skill in the art will understand that the automatedmethod 200 is meant to be illustrative and does not limit the use of themixing apparatus 10 to the type and sequence of steps discussed withrespect to the automated method 200. Rather, the mixing controller 100may use other embodiments of automated methods with the mixing apparatus10 to mix dry media powder into liquid media or, more generally, to mixa dry powder into a liquid. For example, other embodiments of anautomated method for use with the mixing apparatus 10 may include theuse of different solution components, include fewer or additional steps,include different steps, provide the automated method 200 steps in adifferent order, and so on. Further, in other embodiments of anautomated method for use with the mixing apparatus 10, the steps mayinclude different or additional “triggers” for the steps aside fromthose discussed below.

To begin with, all of the valves (e.g., valves 44, 52, 62, 68, 70, 78,and 80) are closed during handling, installation, and setup of themixing apparatus 10 (202). This helps prevent leaking and contaminationduring the setup process of the mixing apparatus 10. During setup, forexample, the first mixing chamber 12 and the second mixing chamber 14,with premeasured amounts of powdered media and sodium bicarbonateprovided in chambers 12 and 14, respectively, are unpackaged and set upas shown in FIG. 1A. Alternatively, the first mixing chamber 12 and thesecond mixing chamber 14 are set up as shown in FIG. 1A and aliquotedamounts of powdered media and sodium bicarbonate are put into thechambers 12 and 14. The first mixing chamber 12 and the second mixingchamber 14 are then configured with the filter 16 and tubing to producethe mixing apparatus 10 as shown in FIG. 1A. Additionally, a compressedair source is coupled to the compressed air entry 42, a purified watersource with a fixed quantity of water is coupled to the water entry 50,and, if desired, a supplement source is coupled to the supplement entry40. A collection vessel is also coupled to the apparatus exit 76.

Next, mixing controller 100 opens the water source, the lower port valve62, and the upper filter inlet valve 80 (204). As shown in FIG. 4A, oncethe water source and the lower port valve 62 are opened, water flowsfrom the water source through the water inlet tube 48 and through thelower port valve 62 into the lower flow tube 54. The water then flowsfrom the lower flow tube 54 into the first mixing chamber 12 via thelower port 24, at which point the water begins mixing with the powderedmedia contained within the first mixing chamber 12.

Additionally, because the upper filter inlet valve 80 is open, as thefirst mixing chamber 12 begins to fill with water from the bottom of thechamber 12, displaced air is evacuated out of the top port 20 of thefirst mixing chamber 12, as shown in FIG. 4B. The evacuated air flowsthrough the top inlet/outlet 30 and through the upper filter inlet tube34. The evacuated air leaves the mixing apparatus 10 by flowing throughthe filter 16 and out of the outlet 74. Alternatively, once thefiltering membrane of the filter 16 becomes wet, the membrane may notallow the passage of air through the membrane and through the filter 16.Accordingly, air may instead leave the mixing apparatus 10 by ahydrophobic vent provided in the filter 16 (e.g., provided in a topsegment of the filter 16). This is beneficial because it reduces theamount of trapped air in the first mixing chamber 12.

Eventually the water flowing into the first mixing chamber 12 by thelower port 24 and mixing with the powdered media to form media solutionfills the first mixing chamber 12. In some embodiments, the first mixingchamber 12 fills with solution soon after the mixing process begins(e.g., during step 204). In other embodiments, the first mixing chamber12 fills with solution later in the mixing process (e.g., after step204). Regardless, once this occurs, the solution follows the same pathas the evacuated air, as shown in FIG. 4B. The solution leaves the firstmixing chamber 12 via the top port 20 and flows through the topinlet/outlet 30, through the upper filter inlet tube 34, and into thefilter 16 by the filtration tubing section 72. After being filtered andsterilized by the filter 16, the solution flows into the outlet 74 andflows out of the mixing apparatus 10 through the apparatus exit 76,where it is collected by the collection vessel. Although not shown inFIGS. 4C-4E, once the solution begins flowing out of the first mixingchamber 12 by the top port 20, the solution continues to flow out of thefirst mixing chamber 12, through the filter 16, and out of the apparatus10 by the apparatus exit 76 so long as water continues to flow into thefirst mixing chamber 12 (e.g., until step 216, discussed below).

After a predetermined amount of elapsed time, the mixing controller 100closes the lower port valve 62 and opens the upper inlet valve 52 (206).For example, in one embodiment, the mixing controller 100 waits oneminute before closing the lower port valve 62 and opening the upperinlet valve 52. As shown in FIG. 4C, this causes the water to stopflowing into the first mixing chamber 12 by the lower port 24. Instead,the water flows from the water inlet tube 48 to the upper inlet 46. Fromthe upper inlet 46, the water flows into the first mixing chamber 12 bythe upper port 22 and continues mixing with the powdered media in thefirst mixing chamber 12. Switching the flow of water into the firstmixing chamber 12 from the lower port 24 to the upper port 22 helpsmaintain an even dissolution rate of the powdered media in the chamber12 without overwhelming the filter 16 with high concentrations ofsolute, undissolved particles, and air, which may happen when the waterflows into the chamber 12 by the lower port 24. Additionally, switchingthe water flow may facilitate a desired and beneficial dissolution rate.

During the above-described steps of the automated method 200, the mixingcontroller 100 continuously monitors the pressure in the upper filterinlet tube 34 (e.g., by the pressure sensor 90). Once the pressure inthe upper filter inlet tube 34 reaches a predetermined level, the mixingcontroller 100 opens the water bypass valve 78 (208). For example, inone embodiment, the mixing controller 100 opens the water bypass valve78 when the pressure in the upper filter inlet tube 34 reaches 20 psig.As shown in FIG. 4D, when this occurs, water continues to flow into thefirst mixing chamber 12 by the upper inlet 46 and the upper port 22.However, water also flows from the water source through the water inlettube 48 and into the lower filter tube 58. From the lower filter tube58, the water mixes with solution flowing out of the first mixingchamber 12 (not shown) where the upper filter inlet tube 34 and thelower filter tube 58 merge. Subsequently, the solution flows into thefilter 16 by the filtration tubing section 72. After filtration, thewater flows out of the apparatus 10 by the outlet 74 and into thecollection vessel. Opening the water bypass valve 78, thereby allowingwater to bypass the first mixing chamber 12 and the second mixingchamber 14 and flow directly to the filter 16, helps reduce backpressurein the filter 16. It also helps maintain the flow necessary for thefirst mixing chamber 12 to function properly.

The mixing controller 100 keeps water bypass valve 78 open for apredetermined amount of time, allowing water to flow directly to thefilter 16. After the predetermined amount of time has elapsed, themixing controller 100 closes the water bypass valve 78 (210). Forexample, in one embodiment, the mixing controller 100 closes the waterbypass valve 78 after two minutes have elapsed. Subsequently, the waterflow directly to the filter 16 ceases, and the mixing apparatus 10 isswitched back to the condition of step 206 as shown in FIG. 4C. Byclosing the water bypass valve 78, the mixing controller 100 helps avoidpremature depletion of the fixed quantity of water required for theautomated method 200 (e.g., a fixed quantity of 1,000 L of purifiedwater).

The mixing controller 100 also continuously monitors the conductivity ofthe solution entering the filter (e.g., by the conductivity sensor 92).Because the solution conductively is related to the solutionconcentration (e.g., a higher solution conductivity indicates a highersolution concentration and vice versa), monitoring the conductivity ofthe solution entering the filter allows the mixing controller 100 toindirectly monitor the concentration of the solution exiting the firstmixing chamber 12. When the conductivity of the solution reaches apredetermined conductivity, the mixing controller 100 closes the upperinlet valve 52 and opens the lower port valve 62 (212). For example, inone embodiment, the mixing controller 100 closes the upper inlet valve52 and opens the lower port valve 62 when the conductivity of thesolution entering the filter is less than or equal to 6 mS/cm.Accordingly, the water flow into the first mixing chamber 12 switchesfrom the upper port 22 to the lower port 24, returning the mixingapparatus 10 back to the condition of step 204 as shown in FIG. 4A.Switching the flow of the water from the upper port 22 to the lower port24 when the solution conductivity reaches 6 mS/cm helps ensure that asufficient concentration of solutes (e.g., powdered media) in thesolution mixing in the first mixing chamber 12 is maintained (e.g., suchthat the fixed quantity of water provided in the water source is notdepleted without the depleted water being mixed into a sufficientlyconcentrated solution).

In addition to monitoring the pressure in the upper filter inlet tube 34and the conductivity of the solution entering the filter 16, the mixingcontroller 100 further continuously monitors the volume of waterconsumed during the execution of the automated method 200 (e.g., by thevolume sensor 94). Once a total predetermined volume of water isconsumed, the mixing controller 100 closes the lower port valve 62,opens the second chamber inlet valve 70, and opens the second chamberoutlet valve 68 (214). For example, in one embodiment, the mixingcontroller 100 closes the lower port valve 62, opens the second chamberinlet valve 70, and opens the second chamber outlet valve 68 once thetotal volume of water consumed is greater than or equal to 800 L. Asshown in FIG. 4E, once this occurs, water flows from the water sourcethrough the water inlet tube 48 and into the second chamber tube 56.From the second chamber tube 56, the water flows into the second mixingchamber 14 via the second chamber lower port 66, where it mixes with thesodium bicarbonate powder in the second mixing chamber 14. Once thesecond mixing chamber 14 fills with water, the solution of water andbicarbonate is pushed out the second chamber top port 64 and into thesecond chamber outlet 60. The bicarbonate solution then flows from thesecond chamber outlet 60 into the lower flow tube 54, finally enteringthe first mixing chamber 12 by the lower port 24. Once the bicarbonatesolution has entered the first mixing chamber 12, the bicarbonatesolution mixes with the water and the powdered media contained therein.In this way, the sodium bicarbonate power (and/or any other additivescontained within the second mixing chamber 14) is dissolved separatelybefore being added to the solution in the first mixing chamber 12.

The mixing controller 100 keeps the valves in this configuration for apredetermined amount of time. After the predetermined amount of time haselapsed, the mixing controller 100 closes the second chamber inlet valve70, closes the second chamber outlet valve 68, and opens the lower portvalve 62 (216). For example, in one embodiment, the mixing controller100 closes the second chamber inlet valve 70, closes the second chamberoutlet valve 68, and opens the lower port valve 62 once at least fiveminutes have passed. This stops the water flow through the second mixingchamber 14 and reopens the water flow from the water source to the firstmixing chamber 12 via the lower port 24, returning the mixing apparatus10 to the configuration of steps 204 and 212 as shown in FIG. 4A.

Finally, once the mixing controller 100 determines (e.g., by the volumesensor 94) that the total volume of water consumed has reached apredetermined total volume, the mixing controller 100 closes the watersource and the upper filter inlet valve 80. The mixing controller 100further opens the compressed air valve 44 and the water bypass valve 78(218). For example, in one embodiment, the mixing controller 100 closesthe water source and the upper filter inlet valve 80 and opens thecompressed air valve 44 and the water bypass valve 78 once 1,000 L ofwater has been consumed during the mixing process. Once this occurs,compressed air flows from the compressed air source into the compressedair inlet 38 by the compressed air entry 42. From the compressed airinlet 38, the compressed air flows into the common inlet 32 and into thefirst mixing chamber 12 by the top inlet/outlet 30 and via the top port20. The compressed air flowing into the first mixing chamber 12evacuates the solution remaining in the chamber 12 out of the chamber 12through the lower port 24 and into the lower flow tube 54. The evacuatedsolution then flows through the lower flow tube 54, into the lowerfilter tube 58, and into the filter 16 by the filtration tubing section72. After being filtered, the solution flows through the outlet 74 andinto the collection vessel coupled to the apparatus exit 76. In thisway, compressed air can be used to evacuate solution remaining in thefirst mixing chamber 12 out of the apparatus 10 and into the collectionvessel, resulting in the collection vessel contents having the targetvolume yield (e.g., of 1,000 L of prepared liquid media).

During any step of the automated method 200, a supplement may be addedto the solution being mixed in the first mixing chamber 12. FIG. 4Gillustrates the flow of a given supplement into the first mixing chamber12. The supplement flows into the supplement inlet 36 of the apparatus10 by the supplement entry 40 and follows the tubing of the supplementinlet 36 into common inlet 32. If the solution mixing in the firstmixing chamber 12 is still contained in the chamber 12, the supplementflows from the common inlet 32 into the top inlet/outlet 30 and into thefirst mixing chamber 12 by the top port 20. If the solution mixing inthe first mixing chamber 12 has filled the chamber 12 and is flowing outof the top port 20, the supplement mixes with the solution flowing outof the chamber 12 in the upper filter inlet tube 34.

However, while the above described automated method 200 is directed tothe reconstitution of powdered cell culture media, it should beunderstood that embodiments of the mixing apparatus 10 may be used withautomated method embodiments to reconstitute a variety of dryingredients into liquids, such as a variety of bioprocess powders intobioprocess solutions. It is further contemplated that the liquidsolvents employed can be water, alcohols, or other organics. Thesolubility characteristics, the solvent to be used, the amount required,and the chemical interactions between the solvent and the reconstitutedchemicals will serve to provide guidelines for the embodiments of theautomated method used to reconstitute the powders and the configurationof the mixing apparatus 10 used with a given automated methodembodiment. Moreover, while the preferred embodiments described hereinadd liquids to dry ingredients for the purpose of reconstituting thosedry ingredients, it is contemplated that the mixing apparatus can workequally well for the reconstitution of a concentrated liquid or asequential combination of a liquid and a powder.

A variety of modified forms of the technology can be constructed fordifferent end uses. For example, the mixing apparatus 10 may includeonly the first mixing chamber 12. Both the powdered media and thesecondary additive, such as sodium bicarbonate, can be provided to thefirst mixing chamber 12 together. Therefore, only one chamber is neededto dissolve the solids in the fluids. As another example, the mixingapparatus 10 may include one or more additional mixing chambers asidefrom the first mixing chamber 12 and the second mixing chamber 14 (e.g.,to separately mix additional secondary additives).

The foregoing description details certain embodiments of the systems,devices, and methods disclosed herein. It will be appreciated, however,that no matter how detailed the foregoing appears in text, the devicesand methods can be practiced in many ways. As is also stated above, itshould be noted that the use of particular terminology when describingcertain features or aspects of the technology should not be taken toimply that the terminology is being redefined herein to be restricted toincluding any specific characteristics of the features or aspects of thetechnology with which that terminology is associated. The scope of thedisclosure should therefore be construed in accordance with the appendedclaims and any equivalents thereof.

It will be appreciated by those skilled in the art that variousmodifications and changes may be made without departing from the scopeof the described technology. Such modifications and changes are intendedto fall within the scope of the embodiments, as defined by the appendedclaims. It will also be appreciated by those of skill in the art thatparts included in one embodiment are interchangeable with otherembodiments; one or more parts from a depicted embodiment can beincluded with other depicted embodiments in any combination. Forexample, any of the various components described herein and/or depictedin the Figures may be combined, interchanged, or excluded from otherembodiments.

The embodiments herein have been described with reference to drawings.The drawings illustrate certain details of specific embodiments thatimplement the systems and methods described herein. However, describingthe embodiments with drawing should not be construed as imposing on thedisclosure any limitations that may be present in the drawings.

With respect to the use of any plural and/or singular terms herein,those having skill in the art can translate from the plural to thesingular and/or from the singular to the plural as is appropriate to thecontext and/or application. The various singular/plural permutations maybe expressly set forth herein for sake of clarity.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims, are generallyintended as “open” terms (e.g., the term “including” should beinterpreted as “including but not limited to,” the terms “comprising”and “having” should, respectively, be interpreted as “comprising atleast” and “having at least,” the term “includes” should be interpretedas “includes but it not limited to,” etc.). It will be furtherunderstood by those within the art that if a specific number of anintroduced claim recitation is intended, such an intent will beexplicitly recited in the claim, and in the absence of such recitationno such intent is present. For example, as an aid to understanding, thefollowing appended claims may contain usage of the introductory phrases“at least one” and “one or more” to introduce claim recitations.However, the use of such phrases should not be constructed to imply thatthe introduction of a claim recitation by the indefinite articles “a” or“an” limits any particular claim containing such introduced claimrecitation to embodiments containing only one such recitation, even whenthe same claim includes the introductory phrases “one or more” or “atleast one” and indefinite articles such as “a” or “an.” In general, “a”and/or “an” should be interpreted to mean “at least one” or “one ormore”; the same holds true for the use of definite articles used tointroduce claim recitations.

Furthermore, in those instances where a convention analogous to “atleast one of A, B, and C, etc.” is used, in general, such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, and C”would include but not be limited to systems that have A alone, B alone,C alone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). In those instances where a conventionanalogous to “at least one of A, B, or C, etc.” is used, in general,such a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, or C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibility of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

For the purpose of this disclosure, the term “coupled” means the joiningof two members directly or indirectly to one another. Such joining maybe stationary or moveable in nature. Such joining may be achieved withthe two members or the two members and any additional intermediatemembers being integrally formed as a single unitary body with oneanother, or with the two members or the two members and any additionalintermediate members being attached to one another. Such joining may bepermanent in nature or may be removable or releasable in nature.

The technology discussed herein has numerous applications and whileparticular embodiments of the technology have been described in detail,it will be apparent to those skilled in the art that the disclosedembodiments may be modified given the design considerations discussedherein. Therefore, the foregoing description is to be consideredexemplary rather than limiting, and the true scope of the invention isthat defined in the following claims.

What is claimed is:
 1. An automated apparatus for preparing a liquidbioprocess solution, comprising: at least one mixing chamber having alower port and an upper port for fluid to enter the at least one mixingchamber; an array of tubing for fluid flow within the system; aplurality of valves provided within the tubing; and a mixing controllercomprising at least a processor and a memory with instructions storedthereon, the mixing controller configured to cause the automatedapparatus to perform a series of sequential mixing steps, the series ofsequential mixing steps causing the preparation of the liquid bioprocesssolution from a dry ingredient and comprising: opening a first valveassociated with the lower port to provide fluid to the at least onemixing chamber through the lower port, and after a predetermined amountof elapsed time, closing the first valve and opening a second valveassociated with the upper port to provide fluid to the at least onemixing chamber through the upper port.
 2. The automated apparatus ofclaim 1, further comprising one or more sensors configured to take oneor more measurements during preparation of the liquid cell culturemedia.
 3. The automated apparatus of claim 2, wherein the one or moresensors comprise at least one of a pressure sensor, a conductivitysensory, a volume sensor, or a timer.
 4. The automated apparatus ofclaim 2, wherein the one or more measurements comprise at least one ofpressure, conductivity, a volume of water consumed during thepreparation, flow rate or elapsed time.
 5. The automated apparatus ofclaim 2, wherein the mixing controller is configured to control theplurality of valves in response to at least one of a measurementdecreasing below, equaling, or exceeding a measurement threshold.
 6. Theautomated apparatus of claim 1, further comprising two or more inlets tothe tubing, each inlet configured to direct a flow of a fluid into theautomated system.
 7. The automated apparatus of claim 6, wherein one ofthe two or more inlets is configured to be coupled to a compressed airsource.
 8. The automated apparatus of claim 7, wherein the mixingcontroller is further configured to open the compressed air source toevacuate prepared liquid bioprocess solution from the automatedapparatus.
 9. The automated apparatus of claim 1, wherein the automatedapparatus comprises at least a first mixing chamber containing the dryingredient and a second mixing chamber containing an additive.
 10. Theautomated apparatus of claim 9, wherein the mixing controller isconfigured to control the plurality of valves such that the additive ismixed with purified water in the second mixing chamber and subsequentlyadded to the first mixing chamber.
 11. The automated apparatus of claim1, wherein the bioprocess solution is cell culture media.
 12. Theautomated apparatus of claim 11, wherein the bioprocess solution isbuffer solution.
 13. The automated apparatus of claim 1, wherein the dryingredient is powdered.
 14. The automated apparatus of claim 1, whereinthe dry ingredient is granulated.